Aberrant folding of proteins is a feature common to many neurodegenerative diseases, including prion disease, Huntington's disease, Alzheimer's disease, and others. Misfolded proteins may adopt several distinct tertiary and quaternary conformations as they progress from a normal monomeric state and ultimately end up in large aggregated protein deposits in the brain. The role of intermediate protein conformations in the disease process remains elusive, especially in prion and Huntington's diseases. In my current research, I have found that prion protein intermediates that are sensitive to protease digestion appear to contribute significantly to disease pathology. Historically, attention in this field has focused primarily on the protease-resistant forms of the prion protein in the disease process. I have also developed a new technique for detecting protease-sensitive pathological intermediates (Colby et. al., PNAS, 2007). During the mentored phase of this application, I propose to apply this technique to study these intermediates'structure and their role in neurodegeneration. I will continue some aspects of this work as I transition to an independent position, and will also begin applying what I have learned to Huntington's disease. My mentor, Dr. Prusiner, has given me leeway to begin some preliminary studies for my independent work during the mentored phase, in order to facilitate my transition to independence. My more long term career research goals are to understand the unifying factors that relate protein misfolding to neurodegeneration in so many diseases, each associated with misfolding of a different protein. Before I begin working in an independent academic position, I need additional time to strengthen my training in the use of mouse models and in structural biology, especially given my background in Chemical engineering. Stanley Prusiner's Institute for Neurodegenerative Diseases at UCSF is an ideal environment for me to obtain this training. Aside from Dr. Prusiner's recognized leadership in this field, there are many critical collaborators affiliated with the IND who will contribute to my training.